Colloquium
⌬FosB: A sustained molecular switch for addiction
Eric J. Nestler*, Michel Barrot, and David W. Self
Department of Psychiatry and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard,
Dallas, TX 75390-9070
The longevity of some of the behavioral abnormalities that char-
acterize drug addiction has suggested that regulation of neural
gene expression may be involved in the process by which drugs of
abuse cause a state of addiction. Increasing evidence suggests that
the transcription factor ⌬FosB represents one mechanism by which
drugs of abuse produce relatively stable changes in the brain that
contribute to the addiction phenotype. ⌬FosB, a member of the Fos
family of transcription factors, accumulates within a subset of
neurons of the nucleus accumbens and dorsal striatum (brain
regions important for addiction) after repeated administration of
many kinds of drugs of abuse. Similar accumulation of ⌬FosB
occurs after compulsive running, which suggests that ⌬FosB may
accumulate in response to many types of compulsive behaviors.
Importantly, ⌬FosB persists in neurons for relatively long periods
of time because of its extraordinary stability. Therefore, ⌬FosB
represents a molecular mechanism that could initiate and then
sustain changes in gene expression that persist long after drug
exposure ceases. Studies in inducible transgenic mice that overex-
press either ⌬FosB or a dominant negative inhibitor of the protein
provide direct evidence that ⌬FosB causes increased sensitivity to
the behavioral effects of drugs of abuse and, possibly, increased
drug seeking behavior. This work supports the view that ⌬FosB
functions as a type of sustained ‘‘molecular switch’’ that gradually
converts acute drug responses into relatively stable adaptations
that contribute to the long-term neural and behavioral plasticity
that underlies addiction.
A ddiction research is focused on understanding the complex
ways in which drugs of abuse change the brain to cause
behavioral abnormalities that characterize addiction. One of the
critical challenges in the field is to identify relatively stable
drug-induced changes in the brain to account for those behav-
ioral abnormalities that are particularly long-lived. For example,
a human addict may be at increased risk for relapse even after
years of abstinence.
The stability of these behavioral abnormalities has led to the
suggestion that they may be mediated, at least in part, through
changes in gene expression (1–3). According to this view,
repeated exposure to a drug of abuse repeatedly perturbs
transmission at particular synapses in the brain that are sensitive
to the drug. Such perturbations eventually signal via intracellular
messenger cascades to the nucleus, where they first initiate and
then maintain changes in the expression of specific genes. A
primary mechanism through which signal transduction pathways
influence gene expression is the regulation of transcription
factors, proteins that bind to regulatory regions of genes and
modify their transcription.
One goal of addiction research, therefore, has been to identify
transcription factors that are altered in brain regions implicated
in addiction after chronic administration of drugs of abuse.
Several such transcription factors have been identified over the
past decade (1–6). The focus of this review is on one particular
transcription factor called ⌬FosB.
Induction of ⌬FosB by Drugs of Abuse
⌬FosB, encoded by the fosB gene, is a member of the Fos family
of transcription factors, which also include c-Fos, FosB, Fra1,
11042–11046 兩 PNAS 兩 September 25, 2001 兩 vol. 98 兩 no. 20
and Fra2 (7). These Fos family proteins heterodimerize with Jun
family proteins (c-Jun, JunB, or JunD) to form active AP-1
(activator protein-1) transcription factors that bind to AP-1 sites
(consensus sequence: TGAC兾GTCA) present in the promoters
of certain genes to regulate their transcription.
These Fos family proteins are induced rapidly and transiently
in specific brain regions after acute administration of many drugs
of abuse (Fig. 1) (8–11). Prominent regions are the nucleus
accumbens and dorsal striatum, which are important mediators
of behavioral responses to the drugs, in particular, their reward-
ing and locomotor-activating effects (12, 13). These proteins
return to basal levels within hours of drug administration.
Very different responses are seen after chronic administration
of drugs of abuse (Fig. 1). Biochemically modified isoforms of
⌬FosB (molecular mass 35–37 kDa) accumulate within the same
brain regions after repeated drug exposure, whereas all other
Fos family members show tolerance (that is, reduced induction
compared with initial drug exposures). Such accumulation of
⌬FosB has been observed for cocaine, morphine, amphetamine,
alcohol, nicotine, and phencyclidine (11, 14–18). There is some
evidence that this induction is selective for the dynorphin兾
substance P-containing subset of medium spiny neurons located
in these brain regions (15, 17), although more work is needed to
establish this with certainty. The 35- to 37-kDa isoforms of
⌬FosB dimerize predominantly with JunD to form an active and
long-lasting AP-1 complex within these brain regions (19, 20).
These ⌬FosB isoforms accumulate with chronic drug exposure
because of their extraordinarily long half-lives (21), and there-
fore persist in the neurons for at least several weeks after
cessation of drug administration. It is interesting to note that
these ⌬FosB isoforms are highly stable products of an immediate
early gene ( fosB). The stability of the ⌬FosB isoforms provides
a novel molecular mechanism by which drug-induced changes in
gene expression can persist despite relatively long periods of
drug withdrawal.
Although the nucleus accumbens plays a critical role in the
rewarding effects of drugs of abuse, it is believed to function
normally by regulating responses to natural reinforcers, such as
food, drink, sex, and social interactions (12, 13). As a result, there
is considerable interest in a possible role of this brain region in
other compulsive behaviors (e.g., pathological overeating, gam-
bling, exercise, etc.). For this reason, we examined whether
⌬FosB is regulated in an animal model of compulsive running.
Indeed, the stable 35- to 37-kDa isoforms of ⌬FosB are induced
selectively within the nucleus accumbens in rats that show
compulsive running behavior.†
This paper was presented at the Inaugural Arthur M. Sackler Colloquium of the National
Academy of Sciences, ‘‘Neural Signaling,’’ held February 15–17, 2001, at the National
Academy of Sciences in Washington, DC.
Abbreviations: AP-1, activator protein-1; AMPA, ␣-amino-3-hydroxy-5-methyl-4-isox-
azolepropionic acid; CREB, cAMP response element binding protein; Cdk5, cyclin-depen-
dent kinase-5.
*To whom reprint requests should be addressed. E-mail: eric.nestler@utsouthwestern.edu.
†Werme, M., Nestler, E. J. & Brene, S. (2001) Soc. Neurosci. Abstr., in press.
www.pnas.org兾cgi兾doi兾10.1073兾pnas.191352698

Fig. 1. Scheme showing the gradual accumulation of ⌬FosB versus the rapid
and transient induction of other Fos family proteins in response to drugs of abuse.
(A) The autoradiogram illustrates the differential induction of these various
proteins by acute stimulation (1–2 hr after a single drug exposure) versus chronic
stimulation (1 day after repeated drug exposure). (B) Several waves of Fos-like
proteins [comprised of c-Fos (52- to 58-kDa isoforms), FosB (46- to 50-kDa iso-
forms), ⌬FosB (33-kDa isoform), and Fra1 or Fra2 (40 kDa)] are induced in nucleus
accumbens and dorsal striatal neurons by acute administration of a drug of abuse.
Also induced are biochemically modified isoforms of ⌬FosB (35–37 kDa); they,
too, are induced (although at low levels) after acute drug administration, but
persist in brain for long periods because of their stability. (C) With repeated (e.g.,
twice daily) drug administration, each acute stimulus induces a low level of the
stable ⌬FosB isoforms, which is indicated by the lower set of overlapping lines that
indicate ⌬FosB induced by each acute stimulus. The result is a gradual increase in
the total levels of ⌬FosB with repeated stimuli during a course of chronic treat-
ment, which is indicated by the increasing stepped line in the graph.
Biochemical Identity of Stable ⌬FosB Isoforms
As mentioned above, the ⌬FosB isoforms that accumulate after
chronic administration of a drug of abuse or compulsive running
show a molecular mass of 35–37 kDa. They can be differentiated
Nestler et al.
Table 1. Behavioral plasticity mediated by ⌬FosB in nucleus
accumbens-dorsal striatum
Increased locomotor activation in response to acute and repeated
cocaine administration.
Increased rewarding responses to cocaine and morphine in
place-conditioning assays.
Increased self-administration of low doses of cocaine.
Increased motivation for cocaine in progressive ratio assays.
Increased anxiolytic responses to alcohol.
Increased compulsive running behavior.
Based on data in refs. 28 and 29.†‡§¶
from the 33-kDa isoform of ⌬FosB that is induced rapidly but
transiently after a single drug exposure (Fig. 1) (14, 19, 22).
Current evidence suggests that the 33-kDa isoform is the native
form of the protein, which is altered to form the more stable 35-
to 37-kDa products (19, 21). However, the nature of the bio-
chemical modification that converts the unstable 33-kDa isoform
into the stable 35- to 37-kDa isoforms has remained obscure. It
has been speculated that phosphorylation may be responsible
(11). For example, induction of ⌬FosB is attenuated in mice
lacking DARPP-32, a striatal-enriched protein (23, 24). Because
DARPP-32 regulates the catalytic activity of protein phospha-
tase-1 and protein kinase A (25, 26), the requirement for this
protein for the normal accumulation of the stable ⌬FosB
isoforms suggests a possible role for phosphorylation in gener-
ation of these stable products.
Role of ⌬FosB in Behavioral Plasticity to Drugs of Abuse
Insight into the role of ⌬FosB in drug addiction has come largely
from the study of transgenic mice in which ⌬FosB can be induced
selectively within the nucleus accumbens and other striatal
regions of adult animals (27, 28). Importantly, these mice
overexpress ⌬FosB selectively in the dynorphin兾substance P-
containing medium spiny neurons, where the drugs are believed
to induce the protein. The behavioral phenotype of the ⌬FosB-
overexpressing mice, which in many ways resembles animals
after chronic drug exposure, is summarized in Table 1. The mice
COLLOQUIUM
show augmented locomotor responses to cocaine after acute and
chronic administration (28). They also show enhanced sensitivity
to the rewarding effects of cocaine and morphine in place-
conditioning assays (11, 28) and will self-administer lower doses
of cocaine than littermates that do not overexpress ⌬FosB.‡ In
contrast, these animals show normal conditioned locomotor
sensitization to cocaine and normal spatial learning in the Morris
water maze (28). These data indicate that ⌬FosB increases an
animal’s sensitivity to cocaine and perhaps other drugs of abuse
and may represent a mechanism for relatively prolonged sensi-
tization to the drugs.
In addition, there is preliminary evidence that the effects of
⌬FosB may extend well beyond a regulation of drug sensitivity
per se to more complex behaviors related to the addiction
process. Mice expressing ⌬FosB work harder to self-administer
cocaine in progressive ratio self-administration assays, suggest-
ing that ⌬FosB may sensitize animals to the incentive motiva-
tional properties of cocaine and thereby lead to a propensity for
relapse after drug withdrawal.‡ ⌬FosB-expressing mice also
show enhanced anxiolytic effects of alcohol,§ a phenotype that
has been associated with increased alcohol intake in humans.
‡Whisler, K., Kelz, M. B., Chen, J. S., Nestler, E. J. & Self, D. W. (1999) Soc. Neurosci. Abstr.
25, 811.
§Roberts, A., Picetti, R., Nestler, E. J., Koob, G. F. (2001) Soc. Neurosci. Abstr., in press.
¶Peakman, M.-C., Colby, C., Duman, R. S., Allen, M. R., Stock, J. L., NcNeish, J. D., Kelz, M. B.,
Chen, J. S., Nestler, E. J. & Schaeffer, E. (2000) Soc. Neurosci. Abstr. 26, 124.
PNAS 兩 September 25, 2001 兩 vol. 98 兩 no. 20 兩 11043
Together, these early findings suggest that ⌬FosB, in addition to
increasing sensitivity to drugs of abuse, produces qualitative
changes in behavior that promote drug-seeking behavior. Thus,
⌬FosB may function as a sustained ‘‘molecular switch’’ that helps
initiate and then maintain crucial aspects of the addicted state.
An important question under current investigation is whether
⌬FosB accumulation during drug exposure promotes drug-
seeking behavior after extended withdrawal periods, even after
⌬FosB levels have normalized (see below).
Adult mice that overexpress ⌬FosB selectively within the
nucleus accumbens and dorsal striatum also exhibit greater
compulsive running compared with control littermates.† These
observations raise the interesting possibility that ⌬FosB accu-
mulation within these neurons serves a more general role in the
formation and maintenance of habit memories and compulsive
behaviors, perhaps by reinforcing the efficacy of neural circuits
in which those neurons function.
⌬FosB accumulates in certain brain regions outside the nu-
cleus accumbens and dorsal striatum after chronic exposure to
cocaine. Prominent among these regions are the amygdala and
medial prefrontal cortex (15). A major goal of current research
is to understand the contributions of ⌬FosB induction in these
regions to the addiction phenotype.
Earlier work on fosB knockout mice revealed that these
animals fail to develop sensitization to the locomotor effects of
cocaine, which is consistent with the findings of the ⌬FosB-
overexpressing mice mentioned above (22). However, the fosB
mutants showed enhanced sensitivity to cocaine’s acute effects,
which is inconsistent with these other findings. Interpretation of
findings with the fosB mutants, though, is complicated by the fact
that these animals lack not only ⌬FosB, but full-length FosB as
well. Moreover, the mutants lack both proteins throughout the
brain and from the earliest stages of development. Indeed, more
recent work supports conclusions from the ⌬FosB overexpress-
ing mice: inducible overexpression of a truncated mutant of
c-Jun, which acts as a dominant negative antagonist of ⌬FosB,
selectively in nucleus accumbens and dorsal striatum shows
reduced sensitivity to the rewarding effects of cocaine.¶ These
findings emphasize the caution that must be used in interpreting
results from mice with constitutive mutations and illustrate the
importance of mice with inducible and cell type-specific muta-
tions in studies of plasticity in the adult brain.
Target Genes for ⌬FosB
Because ⌬FosB is a transcription factor, presumably the protein
causes behavioral plasticity through alterations in the expression
of other genes. ⌬FosB is generated by alternative splicing of the
fosB gene and lacks a portion of the C-terminal transactivation
domain present in full-length FosB. As a result, it was originally
proposed that ⌬FosB functions as a transcriptional repressor
(29). However, work in cell culture has demonstrated clearly that
⌬FosB can either induce or repress AP-1-mediated transcription
depending on the particular AP-1 site used (21, 29–31). Full-
length FosB exerts the same effects as ⌬FosB on certain
promoter fragments, but different effects on others. Further
work is needed to understand the mechanisms underlying these
varied actions of ⌬FosB and FosB.
Our group has used two approaches to identify target genes for
⌬FosB. One is the candidate gene approach. We initially con-
sidered ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) glutamate receptors as putative targets, given the
important role of glutamatergic transmission in the nucleus
accumbens. Work to date has indicated that one particular
AMPA glutamate receptor subunit, GluR2, may be a bona fide
target for ⌬FosB (Fig. 2). GluR2 expression, but not the
expression of other AMPA receptor subunits, is increased in
nucleus accumbens (but not dorsal striatum) upon overexpres-
sion of ⌬FosB (28), and expression of a dominant negative
11044 兩 www.pnas.org兾cgi兾doi兾10.1073兾pnas.191352698
Fig. 2. The AMPA glutamate receptor subunit, GluR2, is a putative target for
⌬FosB. Shown is how ⌬FosB-mediated induction of GluR2 may alter the
physiological responsiveness of nucleus accumbens neurons and lead to sen-
sitized responses to drugs of abuse. According to this scheme, drugs of abuse
produce their acute reinforcing effects via inhibition of nucleus accumbens
neurons. With repeated exposure, the drugs induce ⌬FosB, which regulates
numerous target genes, including GluR2. This increases the proportion of
AMPA receptors (AMPA-R) on nucleus accumbens neurons that contain the
GluR2 subunit, which causes reduced overall AMPA current and reduced Ca2⫹
current. This reduced excitability could render the neurons more sensitive to
the acute inhibitory effects of the drugs and thereby to the drugs’ reinforcing
effects.
mutant attenuates the ability of cocaine to induce the protein.¶
In addition, the promoter of the GluR2 gene contains a con-
sensus AP-1 site that binds ⌬FosB (28). Overexpression of
GluR2 in the nucleus accumbens, by use of viral-mediated gene
transfer, increases an animal’s sensitivity to the rewarding effects
of cocaine, thereby mimicking part of the phenotype seen in the
⌬FosB-expressing mice (28). Induction of GluR2 could account
for the reduced electrophysiological sensitivity of nucleus ac-
cumbens neurons to AMPA receptor agonists after chronic
cocaine administration (32), because AMPA receptors contain-
ing GluR2 show reduced overall conductance and reduced Ca2⫹
permeability. Reduced responsiveness of these neurons to exci-
tatory inputs may then enhance responses to a drug of abuse.
However, the ways in which dopaminergic and glutamatergic
signals in nucleus accumbens regulate addictive behavior remain
unknown; this will require a neural circuit level of understand-
ing, which is not yet available.
Another putative target for ⌬FosB is the gene encoding
dynorphin. As stated earlier, dynorphin is expressed in the subset
of nucleus accumbens medium spiny neurons that show induc-
tion of ⌬FosB. Dynorphin appears to function in an intercellular
feedback loop: its release inhibits the dopaminergic neurons that
innervate the medium spiny neurons, via ␬ opioid receptors
present on dopaminergic nerve terminals in the nucleus accum-
bens and also on cell bodies and dendrites in the ventral
tegmental area (Fig. 3) (33–35). This idea is consistent with the
ability of a ␬ receptor agonist, upon administration into either of
these two brain regions, to decrease drug reward (35). Recent
work has indicated that ⌬FosB decreases the expression of
dynorphin,储 which could contribute to the enhancement of
reward mechanisms seen with ⌬FosB induction. Interestingly,
another drug-regulated transcription factor, CREB (cAMP re-
sponse element binding protein) (2, 3), exerts the opposite
储Shaw, T. Z., Gilden, L., Kelz, M., Chen, J. & Nestler, E. J. (2000) Soc. Neurosci. Abstr. 26, 525.
Nestler et al.
Fig. 3. Dynorphin is a putative target for ⌬FosB. Shown is a ventral tegmen-
tal area (VTA) dopamine (DA) neuron innervating a class of nucleus accum-
bens (NAc) GABAergic projection neuron that expresses dynorphin (DYN).
Dynorphin serves a feedback mechanism in this circuit: dynorphin, released
from terminals of the NAc neurons, acts on ␬ opioid receptors located on nerve
terminals and cell bodies of the DA neurons to inhibit their functioning. ⌬FosB,
by inhibiting dynorphin expression, may down-regulate this feedback loop
and enhance the rewarding properties of drugs of abuse. Not shown is the
reciprocal effect of CREB on this system: CREB enhances dynorphin expression
and thereby attenuates the rewarding properties of drugs of abuse (4). GABA,
␥-aminobutyric acid; DR, dopamine receptor; OR, opioid receptor.
effect: it induces dynorphin expression in the nucleus accumbens
and reduces the rewarding properties of cocaine and morphine
(4).** Because drug-induced activation of CREB dissipates
rapidly after drug administration, such reciprocal regulation of
dynorphin by CREB and ⌬FosB could explain the reciprocal
behavioral changes that occur during early and late phases of
withdrawal, with negative emotional symptoms and reduced
drug sensitivity predominating during early phases of with-
drawal, and sensitization to the rewarding and incentive moti-
vational effects of drugs predominating at later time points.
The second approach used to identify target genes for ⌬FosB
involves DNA microarray analysis. Inducible overexpression of
⌬FosB increases or decreases the expression of numerous genes
in the nucleus accumbens (36). Although considerable work is
now needed to validate each of these genes as physiologic targets
of ⌬FosB and to understand their contribution to the addiction
phenotype, one important target appears to be Cdk5 (cyclin-
dependent kinase-5). Thus, Cdk5 was initially identified as
⌬FosB-regulated by use of microarrays, and later shown to be
induced in nucleus accumbens and dorsal striatum after chronic
cocaine administration (37). ⌬FosB activates the cdk5 gene via
an AP-1 site present within the gene’s promoter (36). Together,
these data support a scheme wherein cocaine induces Cdk5
expression in these brain regions via ⌬FosB. Induction of Cdk5
appears to alter dopaminergic signaling at least in part via
increased phosphorylation of DARPP-32 (37), which is con-
verted from an inhibitor of protein phosphatase-1 to an inhibitor
of protein kinase A upon its phosphorylation by Cdk5 (26).
Role of ⌬FosB in Mediating ‘‘Permanent’’ Plasticity to Drugs
of Abuse
Although the ⌬FosB signal is relatively long-lived, it is not
permanent. ⌬FosB degrades gradually and can no longer be
detected in brain after 1–2 months of drug withdrawal, even
though certain behavioral abnormalities persist for much longer
periods of time. Therefore, ⌬FosB per se would not appear to be
able to mediate these semipermanent behavioral abnormalities.
**Barrot, M., Olivier, J. D. A., Zachariou, V., Neve, R. L. & Nestler, E. J. (2000) Soc. Neurosci.
Abstr. 26, 485.
Nestler et al.
Fig. 4. Regulation of dendritic structure by drugs of abuse. Shown is the
expansion of a neuron’s dendritic tree after chronic exposure to a drug of
abuse, as has been observed with cocaine in the nucleus accumbens and
prefrontal cortex (41). The areas of magnification show an increase in den-
dritic spines, which is postulated to occur in conjunction with activated nerve
terminals. This increase in dendritic spine density may be mediated via ⌬FosB
and the consequent induction of Cdk5 (see text). Such alterations in dendritic
structure, which are similar to those observed in some learning models (e.g.,
long-term potentiation), could mediate long-lived sensitized responses to
drugs of abuse or environmental cues. [Reproduced with permission from ref.
3 (Copyright 2001, Macmillian Magazines Ltd.)].
The difficulty in finding the molecular adaptations that underlie
the extremely stable behavioral changes associated with addic-
tion is analogous to the challenges faced in the learning and
memory field. Although there are elegant cellular and molecular
models of learning and memory, it has not to date been possible
to identify molecular and cellular adaptations that are suffi-
ciently long-lived to account for highly stable behavioral mem-
ories. Indeed, ⌬FosB is the longest-lived adaptation known to
occur in adult brain, not only in response to drugs of abuse, but
to any other perturbation (that doesn’t involve lesions) as well.
Two proposals have evolved, both in the addiction and learning
and memory fields, to account for this discrepancy.
COLLOQUIUM
One possibility is that more transient changes in gene
expression, such as those mediated via ⌬FosB or other tran-
scription factors (e.g., CREB), may mediate more long-lived
changes in neuronal morphology and synaptic structure. For
example, an increase in the density of dendritic spines (par-
ticularly an increase in two-headed spines) accompanies the
increased efficacy of glutamatergic synapses at hippocampal
pyramidal neurons during long-term potentiation (38 – 40),
and parallels the enhanced behavioral sensitivity to cocaine
mediated at the level of medium spiny neurons of the nucleus
accumbens (41). It is not known whether such structural
changes are sufficiently long-lived to account for highly stable
changes in behavior, although the latter persist for at least 1
month of drug withdrawal. Recent evidence raises the possi-
bility that ⌬FosB, and its induction of Cdk5, is one mediator
of drug-induced changes in synaptic structure in the nucleus
accumbens (Fig. 4).†† Thus, infusion of a Cdk5 inhibitor into
the nucleus accumbens prevents the ability of repeated cocaine
exposure to increase dendritic spine density in this region. This
is consistent with the view that Cdk5, which is enriched in
brain, regulates neural structure and growth (see refs. 36 and
37). It is possible, although by no means proven, that such
changes in neuronal morphology may outlast the ⌬FosB signal
itself.
††Norrholm, S.D., Bibb, J. A., Nestler, E. J., Ouimet, C. C., Taylor, J. R. & Greengard, P. (2001)
Soc. Neurosci. Abstr., in press.
PNAS 兩 September 25, 2001 兩 vol. 98 兩 no. 20 兩 11045
 Another possibility is that the transient induction of a tran-
scription factor (e.g., ⌬FosB, CREB) leads to more permanent
changes in gene expression through the modification of chro-
matin. These and many other transcription factors are believed
to activate or repress the transcription of a target gene by
promoting the acetylation or deacetylation, respectively, of
histones in the vicinity of the gene (42). Although such acety-
lation and deacetylation of histones can apparently occur very
rapidly, it is possible that ⌬FosB or CREB might produce
longer-lasting adaptations in the enzymatic machinery that
controls histone acetylation. ⌬FosB or CREB may also promote
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